Vitamin A (retinol) and most derivatives thereof having vitamin A activity are water-insoluble, being hydrophobic, lipid-soluble compounds. For example, retinoic acid is not water-soluble. It is known, however, that the glucuronide and glucose derivatives of retinoic acid and retinol are water-soluble. [See, for example, Lippel and Olson, J. Lipid. Res., 9:580-586 (1968); Takabayashi, et al. Chem. Abs. 73:69834z (1970); Barua, et al., Amer. J. Clin. Nutr., 43:481-485 (1986).] Water-soluble glycoside derivatives of vitamin A are described in U.S. Pat. No. 4,457,918. The retinoic acid glucuronide and retinol glucuronide have been tested for effects in vitro on cultures of HL-60 cells (a continuous human myeloid cell line): Gallup, et al., First Mid-America Molecular Biol. Colloquium, p. 35, October 1986, and Proc. Soc. Exper. Biol. & Med., 186:269-274 (1987); and Zile, et al., Proc. Nat. Acad. Sci. USA, 84:2208-2212 (1987). Under the conditions of the HL-60 systems assay, activity similar to retinoic acid and retinol was reported. Both Gallup, et al. and Zile, et al. found that retinoyl .beta.-glucuronide (retinoic acid glucuronide) was 50% less cytotoxic to HL-60 cells than all-trans retinoic acid.
The all-trans form of retinoic acid has been named tretinoin. Cream, gel, and liquid preparations containing tretinoin have been approved in the United States for treatment of acne. These preparations are being marketed under the trademark "Retin-A" by the Dermatological Division of Ortho Pharmaceutical Corporation, Raritan, N.J. The 13-cis form of retinoic acid has been named isotretinoin. Its use has been approved in the United States for oral treatment of severe acne (e.g., disfiguring cystic acne). Isotretinoin is marketed under the trademark "Accutane" by Roche Laboratories, Nutley, N.J., in 10, 20 and 40 milligram (mg) capsules. A typical dose range is from 0.5 to 2 mg/kg body weight per 24 hours. At these dose levels, isotretinoin is highly teratogenic.
When women of child-bearing age are being treated with isotretinoin for acne, extreme caution must be exercised to avoid the occurrence of a pregnancy during the treatment or at least one month after the treatment is discontinued. It is recommended that such woman patients not be treated with oral isotretinoin unless they agree to mandatory contraceptive measures and have had a negative serum pregnancy test prior to beginning the therapy. Major human fetal abnormalities relating to "Accutane" administration have been reported, and there is also an increased risk of spontaneous abortion. Other vitamin A congeners are also known to be teratogenic in animals and women. [See the teratogen update published by Rosa, et al., in Teratology, 33:355-364 (1986)].